The Mammalian target of rapamycin (mTOR) is a vital effector of the PI3K/AKT/mTOR pathway involved in regulating many cellular processes that promote tumorigenesis such as cancer cell survival, proliferation, and growth. The PI3K/AKT/mTOR pathway is normally regulated by upstream receptor tyrosine kinases, especially insulin receptor and insulin-like growth factor-1 receptor (IGF-1R). Recent in vitro and in vivo studies, as well as tumor biopsy results from patients, have demonstrated that treatment with mTOR inhibitors leads to upregulation of AKT phosphorylation in tumors. Given that AKT activation results in increased malignant phenotype, the induction of phosphorylated AKT (pAKT) is an undesirable consequence of mTOR inhibition, antagonizing the anti-proliferative effects of mTOR inhibitors. Several studies have shown that mTOR inhibitors mediate AKT activation through an IGF-1R-dependent mechanism and that IGF-1R inhibitors may abrogate or reduce pAKT induced by mTOR inhibitors. Therefore, combining an IGFR inhibitor with an mTOR inhibitor could overcome AKT-mediated tumor escape/ resistance. We will perform the first study of the combination of the mTOR inhibitor temsirolimus (CCI-779) and the IGF-1R Inhibitor monoclonal antibody IMC-A12. This protocol was developed in response to a National Cancer Institute-Cancer Therapeutics Evaluation Program (NCI-CTEP) solicitation and has been approved by NCI-CTEP. The primary research objective of this project is to evaluate pharmacodynamic markers of the antitumor/biologic activity of IMC-A12 and temsirolimus upon combined administration to patients with advanced malignancies. Patients will be followed for evaluation of toxicity, tolerability and clinical benefit of IMC-A12 and temsirolimus. We will evaluate pharmacodynamic markers including pAKT and signaling components in the IGF-1R and PI3K/AKT/mTOR pathways by reverse phase protein array, immunohistochemistry, as well as early changes in tumor glucose metabolism by 2[18F]fluoro-2-deoxy-D-glucose Positron Emission Tomography. The results of these studies will be incorporated into designs for expanded clinical trials with IMC-A12 + temsirolimus. PUBLIC HEALTH RELEVANCE: The results of this trial will provide further insight regarding tumor resistance to drugs as well as strategies that can be used to overcome such resistance. A better understanding of tumor metabolism detected by non-invasive imaging will also be delineated. The proposed study has the potential to be a signature trial for future combinations of IGF-R and mTOR inhibitors, including small molecule IGF-R inhibitors, and to provide data to define the optimum correlative endpoints for such trials. The drug combination tested in this protocol has the promise of providing broad applicability for tumor types such as breast, sarcoma and pancreas in subsequent phase II trials.